Role of p53 in the ability of 1,2-diaminocyclohexane-diacetato-dichloro-Pt(IV) to circumvent cisplatin resistance

Several reports indicate that the mechanism of resistance to cisplatin is m ultifactorial. However, DNA damage tolerance appears to be the more signifi cant mechanism. It is clear that resistance in general is a major clinical concern, and a number of approaches have been taken to circumvent this clin ical impediment. One approach is through analog development, and we have id entified 1,2-diaminocyclohexane-diacetatodichloro-platinum(IV) as an analog with activity in cisplatin resistance. The activity is greatest against ov arian tumor cell lines where the latent, non-inducible wild-type p53 functi on can be reactivated by the analog. This functional activation of p53 also corresponds to a reduced threshold for tolerance to DNA damage induced by the analog. Interestingly, cell lines with mutant or null p53 are cross-res istant to the analog. The data indicate that cisplatin resistance due to an increase in DNA damage tolerance can arise through a loss of p53 function, and that functional activation of latent wild-type p53 by the analog facil itates cell death and circumvents this resistance mechanism. (C)1999 Elsevi er Science Inc. All rights reserved.